Tricyclic antidepressants are still a dominating group of psychotherapeutic drugs used in the treatment of depression. Oral dryness is one of their major side-effects, leading in humans to increased oral disease and dysfunction of speech, chewing, swallowing and taste. We previously reported that the tricyclic antidepressant desipramine desensitizes beta-adrenergic signal transduction in salivary glands. In this study, we evaluated the effects of this treatment on parotid and submandibular gland function, oral microbiota, and oral health in rats. Total protein secretion and salivary alpha-amylase was not affected by treatment, while cellular alpha-amylase and the content of epidermal growth factor was depressed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed increased secretion for proline-rich proteins and glycoproteins. Surprisingly, flow rates were temporarily increased. These alterations in salivary gland function may partially explain the observed changes in oral microbiota and the increased incidence of gingivitis. Under other nutritional conditions, desipramine might have more severe impacts on oral health.